The emergence of subunit vaccines, including polypeptide, polysaccharide, conjugate, and DNA vaccines, has intensified the need for safe and effective adjuvant-containing compositions.
Currently, the most commonly used adjuvants in the United States are alum adjuvants (i.e., aluminum salts such as aluminum hydroxide and aluminum phosphate). Only alum is currently approved for human use by the U.S. Department of Health and Human Services, Food and Drug Administration (FDA). For example, various diphtheria-tetanus vaccines are available in which diphtheria toxoids and tetanus toxoids are adsorbed to aluminum salts. Although aluminum adjuvants have a demonstrated safety profile of many years, these adjuvants are nonetheless occasionally associated with local reactions. For example, post-vaccination granulomas are a well-known reaction associated with aluminum-adsorbed vaccines.
Particulate carriers have been used with adsorbed or entrapped antigens in attempts to elicit adequate immune responses. Such carriers typically present multiple copies of a selected recombinant protein antigen to the immune system and promote trapping and retention of antigens in local lymph nodes. The particles can be phagocytosed by macrophages and can enhance antigen presentation through cytokine release.
For example, commonly owned International patent application WO 98/33487 and co-pending U.S. patent application Ser. No. 09/015,652, filed Jan. 29, 1998, describe the use of antigen-adsorbed and antigen-encapsulated microparticles to stimulate immunological responses, including cell-mediated immunological responses, as well as methods of making the microparticles. Polymers used to form the microparticles include poly(lactide) and poly(lactide-co-glycolide), also referred to herein as “PLG”.
Commonly owned International patent application WO 00/06123 and co-pending U.S. patent application Ser. No. 09/715,902 disclose methods of making microparticles having adsorbed macromolecules, including DNA, polypeptides, antigens and adjuvants. The microparticles comprise, for example, a polymer such as a poly(alpha-hydroxy acid) (e.g., PLG), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester, a polyanhydride, and the like and are formed using, for example, cationic, anionic or nonionic detergents. Microparticles containing anionic detergents, such as PLG microparticles with sodium dodecyl sulfate (SDS), are proposed for the use of positively charged macromolecules, such as polypeptides. Microparticles containing cationic detergents, such as PLG microparticles with CTAB (cetyltrimethylammonium bromide), are proposed for the use of negatively charged macromolecules, such as DNA. The use of such microparticles to stimulate immunological responses, including cell-mediated immunological responses, is also disclosed.